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Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma

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Item Type:Article
Title:Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma
Creators Name:Ng, Y.L.D. and Ramberger, E. and Bohl, S.R. and Dolnik, A. and Steinebach, C. and Conrad, T. and Müller, S. and Popp, O. and Kull, M. and Haji, M. and Gütschow, M. and Döhner, H. and Walther, W. and Keller, U. and Bullinger, L. and Mertins, P. and Krönke, J.
Abstract:The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are highly effective treatments for multiple myeloma. However, virtually all patients eventually relapse due to acquired drug resistance with resistance-causing genetic alterations being found only in a small subset of cases. To identify non-genetic mechanisms of drug resistance, we here perform integrated global quantitative tandem mass tag (TMT)-based proteomic and phosphoproteomic analyses and RNA sequencing in five paired pre-treatment and relapse samples from multiple myeloma patients. These analyses reveal a CDK6-governed protein resistance signature that includes myeloma high-risk factors such as TRIP13 and RRM1. Overexpression of CDK6 in multiple myeloma cell lines reduces sensitivity to IMiDs while CDK6 inhibition by palbociclib or CDK6 degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with IMiDs in vitro and in vivo. This work identifies CDK6 upregulation as a druggable target in IMiD-resistant multiple myeloma and highlights the use of proteomic studies to uncover non-genetic resistance mechanisms in cancer.
Keywords:ATPases Associated with Diverse Cellular Activities, Cell Cycle Proteins, Cyclin-Dependent Kinase 6, Immunologic Factors, Lenalidomide, Local Neoplasm Recurrence, Multiple Myeloma, Proteomics, Ubiquitin-Protein Ligases, Up-Regulation
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:1009
Date:23 February 2022
Official Publication:https://doi.org/10.1038/s41467-022-28515-1
PubMed:View item in PubMed

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